The goal of this research proposal is to develop a strategy to use patient derived cells with defined disease genotypes to identify disrupted molecular pathways through large-scale proteomics and network analysis. We have named this approach proteogenetics. Human induced pluripotent stem cells (hiPSC) have revolutionized the ability to study human diseases from patients. It is now possible to obtain fibroblasts from patients suffering from a disease and to reprogram the cells to pluripotent stem cells and then differentiate them into a cell type associated with the disease state. This reverses a long standing limitation for the study of human diseases has been the ability to use cells directly from patients with the appropriate disease phenotype and genotype. To study Rett's syndrome, we will combine vertical (unaffected parent and affected child) and horizontal genetics (different mutations in families/patients) to measure proteomic changes in affected forebrain neuronal cells (FNC) derived through fibroblasts and hiPSCs. For schizophrenia, we will use cells from several patients, but will not have access to unaffected parents. We will use network analysis techniques to identify pathway based phenotypic differences from protein and phosphoprotein expression patterns. Fibroblasts have been obtained from unaffected parents and affected children for Rett's syndrome and schizophrenia patients by Professor Allyson Moutri's (UCSD) and Professor Fred Gage's laboratory (The Salk Institute), respectively. These cells have been reprogrammed to iPSCs and differentiated into forebrain neurons for proteomic analysis. Our hypothesis is that this approach will identify specific molecular processes disrupted by disease.